Impact and Therapeutic Potential of PPARs in Alzheimers Disease

Abstract

Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism, but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer’s disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD.

Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease: Possible role of 4-hydroxynonenal (4-HNE)

“…PPARβ/δ seems to works as sensor of oxidative stress, this phenomenon being apparent at 3 mo age in Tg mice, typically characterized by the appearance of oxidative stress, [17][18][19][20][21][22] even though in the present study this event is not correlated with cell death, as apoptotic nuclei are not detected by TUNEL analysis at this age. Therefore, it appears that in the neocortex at 3 mo age, the increased levels of PPAR β/δ and the absence of an increase of 4-HNE adducts protect this brain area from the early perturbation of the redox status.…”

“…Indeed, their involvement in neurodegenerative Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer, Parkinson, and Huntington diseases, is well recognized. [15][16][17][18][19][20][21][22] Even though PPAR β/δ is the most abundant isotype in the developing and adult central nervous system (CNS), [23][24][25] its role in neurodegenerative diseases remains unclear. We have previously demonstrated that PPAR β/δ is crucial for neuronal maturation, and that its expression affects the BDNF signaling pathway.…”

MK886 Reduces Cerebral Amyloid Angiopathy Severity in TgCRND8 Mice

“…Activation of PPARs by fatty acids and leukotrienes has been shown to lower plasma triglyceride levels, elevate HDL cholesterol levels, reduce serum glucose levels and promote adipocyte differentiation [24,25]. Additionally, levels of cholesterol-related proteins such as apoE, ATP-binding cassette transporter (ABC) A1 and ABCG1 and LRP-1 are regulated by PPAR expression [26,27].…”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…The role of neuroinflammation in AD pathogenesis was highlighted by multiple epidemiological and animal studies in which NSAIDs had substantial sparing effects on AD neurodegeneration (Etminan et al 2003;McGeer & McGeer 2013). Furthermore, neuroprotective effects of other classes of anti-inflammatory drugs were demonstrated in models of AD (Heneka et al 2011).…”